Hyperglycemia and the Acute Ischemic Penumbra
September 1, 2002 4 minutes read
Abstracts & Commentary
Sources: Parsons MW, et al. Acute hyperglycemia adversely affects stroke outcome: A magnetic resonance imaging and spectroscopic study. Ann Neurol. 2002;52:20-28; Ginsberg MD. Hyperglycemia and stroke outcome: Vindication of the ischemic penumbra. Ann Neurol. 2002;52:5-6.
Over the past 25 years, many experimental studies and clinical surveys of acute ischemic stroke have confirmed the observation of Myers and Yamaguchi (Myers RE, Yamaguchi S. Arch Neurol. 1977;34:65-74) that elevated plasma glucose levels coincident with acute ischemia are associated with a worse outcome.
The senior editor of Neurology Alert and his collaborators, among others, previously reported that hyperglycemia augments ischemic brain damage in rats (Pulsinelli WA, et al. Neurology. 1982;32:1239-1246) and in acute stroke patients whether or not they had established diabetes mellitus (Pulsinelli WA, et al. Am J Med. 1983;74:540-544).
The postulated mechanism of neuronal injury is that during ischemia, elevated brain glucose levels in conjunction with an ischemia-induced shift to anaerobic glycolysis lead to severe tissue lactic acidosis which, in turn, leads to tissue necrosis. Therefore, one would predict that hypoperfused brain tissue or the acute ischemic penumbra should produce increased levels of lactic acid during hyperglycemia because of ongoing delivery of glucose to ischemic tissue capable only of anaerobic metabolism.
Studies in humans prior to the advent of magnetic resonance imaging (MRI) were unable to establish that hyperglycemia in acute ischemic stroke promotes the infarction of hypoperfused but potentially viable brain tissue. At present, MRI with perfusion-weighted imaging (PWI), diffusion weighted imaging (DWI), and MR spectroscopy provide the means to examine the relationship between hyperglycemia and infarction in humans.
Patients imaged at the hyperacute stage of stoke typically demonstrate PWI > DWI lesion mismatch which the authors have postulated to be the MRI image of the penumbra (Barber PA, et al. Neurology. 1988;51:418-426). During the first 24 hours after stroke onset, some of the PWI lesion becomes DWI positive and the rest of the PWI area contracts due to reperfusion and tissue salvage. MR spectroscopy detects both the presence of lactate in brain tissue within minutes of the onset of cerebral ischemia, and serial increases in lactate levels when ongoing ischemia leads to continuing lactate production (Parsons MW, et al. Neurology. 2000;55:498-505).
Parsons et al performed prospective serial PWI, DWI, MR spectroscopy, and blood glucose studies in 63 acute stroke patients. The presence of acute PWI > DWI mismatch was used to identify hypoperfused at risk of infarction tissue or penumbra. In 40 of 63 patients with acute PWI > DWI mismatch, acute hyperglycemia was correlated with reduced salvage of penumbra from infarction, greater final infarct size, and worse functional outcome. There was a strong independent relationship between increasing acute blood glucose and reduced penumbral salvage such that a doubling of blood glucose from 5 to 10 mm/L led to a 60% reduction in penumbral salvage.
Higher acute blood glucose in patients with PWI > DWI mismatch was associated with greater lactate production. This also was independently associated with reduced salvage of at-risk tissue. In nonmismatch patients (PWI = DWI) without an ischemic penumbra, acute blood glucose levels did not correlate with outcome nor was there any increasing lactate production in this group. Therefore, as pointed out by Ginsberg in his editorial, these results establish that the deleterious influence of acute hyperglycemia is on penumbral tissue and is reflected in increased acute tissue lactate production.
Commentary
Although some clinical studies have concluded that hyperglycemia adversely affects the outcome of acute ischemic stroke, others have not found it to be an independent risk factor but rather an epi phenomenon or marker of a catecholamine-mediated stress response to a more severe stroke (Tracey F, Stout RQ. Stroke. 1994; 25:524-525). The study of Parsons et al further establishes the clinical danger of hyperglycemia and defines both the probable mechanism of injury by means of lactic acidosis and the site of action as the ischemic penumbra. The ischemic penumbra as defined by Ginsberg is "a hypoperfused, clinically and metabolically unstable tissue region potentially at risk of irreversible injury, yet capable of salvage in response to acute measures taken to increase perfusion and/or confer metabolic neuroprotection."
Hyperglycemia in acute stroke appears to deserve aggressive management that must be initiated as soon as possible, that is, within the same "therapeutic window" as thrombolytic treatment. The practical implementation of acute measures to reduce elevated blood glucose levels requires care lest over aggressive treatment produce even more deleterious hypoglycemia. —John J. Caronna
Dr. Caronna, Vice-Chairman, Department of Neurology, Cornell University Medical Center; Professor of Clinical Neurology, New York Hospital, is Associate Editor of Neurology Alert.
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